CS204032B2 - Method of producing novel imidazo-isoquinolidines - Google Patents

Abstract

Compounds of the formula <IMAGE> wherein R1 is lower alkyl; phenyl-lower alkyl; cycloalkyl of 3 to 6 carbon atoms; phenyl; mono- or di-substituted phenyl, where the substituents, which may be identical to or different from each other, are each halogen, hydroxyl, methoxy, methylmercapto, methylsulfinyl, methylsulfonyl or benzyloxy; and A is hydrogen or <IMAGE> where R2 is hydrogen or lower alkyl; R3 is lower alkyl or dimethoxyphenyl-lower alkyl; or R2 and R3, together with each other and the nitrogen atom to which they are attached, are piperidino, morpholino or N'-lower alkyl-piperazino; and n is 2 or 3; and non-toxic, pharmacologically acceptable acid addition salts thereof. The compounds as well as their salts are useful as cardiotonics, hypotensives, antithrombotics and antiarrhythmics.

Description

The invention relates to novel imidazo-isoquinolinediones of the general formula I

in which

R 1 represents an alkyl group having 1 to 3 carbon atoms optionally substituted by a phenyl group, a cycloalkyl group having 3 to 6 carbon atoms or a phenyl group optionally substituted by one or two of the same or different substituents selected from halogen, hydroxyl, methoxy, methylmercaptoscycline, methylsulfinyl, methylsulfonyl and benzyloxy,

A represents a hydrogen atom or a moiety of the formula

Rž

Z - (CH 2) n -N

R3 where

R 2 represents a hydrogen atom or a C 1 -C 3 alkyl group,

R 3 represents a C 1 -C 3 alkyl group optionally substituted by a dimethoxyphenyl group; or

R 2 and R 5 together with the nitrogen atom to which they are attached form a piperidino, morpholino or piperazino group, wherein the piperazino group is substituted in the 4-position with an alkyl group having 1 to 3 carbon atoms, and n is an integer of 2 or 3; physiologically tolerable addition salts with inorganic or organic acids, processes for the preparation of these substances and medicaments containing them as active ingredients.

The compounds of formula I have valuable pharmacological properties, in addition to anxiolytic action, in particular a cardiovascular action. Thus, compounds of formula I in which A represents a hydrogen atom show, in particular, a cardiotonic effect, lowering blood pressure and, in 204032, inhibit platelet aggregation, and compounds of formula I in which A represents a grouping

Ra \

N- (CH2) n-

R 3 in particular have an antiarrhythmic effect. In addition, the compounds of formula I wherein A is hydrogen are valuable intermediates for the preparation of imidazo-isoquinolinediones substituted at the 5-position with an aminoalkyl radical.

The term "halogen atom" used in the definition of the meaning of the symbol R 1 means in particular fluorine, chlorine or bromine atoms.

Thus, R 1, R 2 and R 3 are, in particular, for R 1, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl,

1-phenylethyl, 1-phenylpropyl, 2-phenylethyl, 2-phenylpropyl, 3-phenylpropyl, 3-phenyl-2-propyl, phenyl, methoxyphenyl, dimethoxyphenyl, chlorophenyl, dichlorophenyl, fluorophenyl, difluorophenyl, hydroxyphenyl, dihydroxyphenyl, bromophenyl, bromophenyl, bromophenyl chlorbromfenylová, methylmerkaptofenylová, bismethylmerkaptofenylová, methylsulfinylfenylová, blsmethylsulfinylfenylová, methylsulfonylphenyl, bisimethylsulfonylfenylová, benzyloxyphenyl, dibenzyloxyfenylová, hydroxymethoxyfenylová, hydroxy methylmerkaptofenylová, methylsulfinylfenylová hydroxy, hydroxy-methylsulfonylphenyl, hydroxy-benzyloxyphenyl, hydroxy-chlorophenyl, bromophenyl hydroxy, methoxy methylmerkaptofenylová, methoxy- methylsulfinylphenyl, methoxy-methylsulfonylphenyl, methoxy-benzyloxyphenyl, methoxy-chlorophenyl, methoxy-fluorophenyl, methoxy-bromophenyl, methyl mercapto-methylsulfinylphenyl, methyl mercapto-methylsulfonylphenyl , methyl mercapto-benzyloxyphenyl, methyl mercapto-chlorophenyl, methyl mercapto-bromophenyl, methylsulfinyl-methylsulfonylphenyl, methylsulfinyl-chlorophenyl, methylsulfinyl-bromophenyl, methylsulfinyl-benzyloxyphenyl, methylsulfonyl-chlorophenyl or methylsulfonylpropyl, methylsulfonylpropyl, methylsulfonylpropyl, methylsulfonylpropyl, methylsulfonylpropyl, methylsulfonylpropyl, methylsulfonylpropyl, and for R3, methyl, ethyl, propyl, isopropyl, dimethoxybenzyl, 1- (dimethoxyphenyl) ethyl, 2- (dimethoxyphenyl) ethyl, 3- (dimethoxyphenyl) propyl, or

3- (dimethoxyphenyl) -2-propyl, and for Rž and R společné together with the nitrogen atom of the piperidino, morpholino, N-methylpiperazino,--ethylpiperazino, N-propylpiperazino or N-isopropylpiperazino group.

Particularly preferred compounds of formula I are those in which:

R 1 represents a methyl, ethyl, benzyl, 1-phenylethyl, 2-phenylethyl, cyclopropyl, cyclohexyl, 4-chlorophenyl, 2-methoxy-5-methylsulfinylphenyl or 2-methoxy-5-methylsulfonylphenyl group, or a phenyl group which may be in the position 2 and / or 4 mono- or disubstituted by methoxy, hydroxyl, methylmercapto, methylsulfinyl or / and methylsulfonyl,

A represents a hydrogen atom or a moiety

Rž /

_ (CH 2) n -N

R3 where

R 2 represents a hydrogen atom, a methyl, ethyl or propyl group,

R 3 represents a methyl, ethyl, propyl or 2- (3,4-dimethoxyphenyl) ethyl group;

R 2 and R 3 together with the nitrogen atom to which they are attached form a piperidino, morpholino or N-methylpiperazino group and n is a number of 2 or 3.

In accordance with the invention, the novel compounds of formula I are prepared by the preparation of a dicarboxylic acid of formula II

in which

Rt is as defined above, or a reactive derivative thereof, such as an anhydride, esters, amide, imide or halide, is reacted with an amine of formula III

A — NH2 (III) in which

A is as defined above.

Depending on the starting dicarboxylic acid derivative of the formula (II) used, the reaction is carried out at a temperature of between and 250 DEG C., optionally in a solvent such as tetralin or ethylene glycol, but preferably in the melt. If the starting material is a carboxylic acid of the formula II, the reaction is preferably carried out with boiling ethylene glycol. However, the reaction can also be carried out using the appropriate ammonium salt of the carboxylic acid of formula II, which is conveniently prepared by reacting the carboxylic acid of formula II with concentrated ammonia (see Example 1), or using the corresponding amide, at elevated temperature or the presence of a water cleaving agent such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid or phosphorus oxychloride.

According to the process of the present invention, compounds of formula I in which R 1 is a phenyl group substituted with methyl mercapto can be converted to the corresponding methylsulfinyl or methylsulfonyl derivatives of formula I by treatment with one or two equivalents of an oxidizing agent; the compound of formula I in which R 1 is phenylsubstituted with methylsulphinyl may be converted by treatment with an oxidizing agent to the corresponding methylsulfonyl derivative of formula I, and / or the compound of formula I in which R 1 is phenylsubstituted with benzyloxy may be debenzylated convert to the corresponding hydroxy derivative.

The subsequent oxidation of the corresponding compound of formula (I) is conveniently carried out in a solvent such as glacial acetic acid or a mixture of water and glacial acetic acid by treatment with an oxidizing agent such as hydrogen peroxide, optionally in the presence of an alkali metal acetate such as sodium acetate. 0 to 100 ° C, preferably at a temperature between 10 and 50 ° C.

The subsequent debenzylation of the corresponding compound of formula (I) is conveniently carried out in a solvent such as methanol or ethyl acetate by treatment with catalytically activated hydrogen, for example hydrogen in the presence of palladium on carbon at a hydrogen pressure of 0.3 to 0.6 MPa and at a temperature 40-60 ° C.

The compounds of formula (I) obtained by the process of the invention can further be converted into physiologically tolerable salts with inorganic or organic acids. Examples of suitable acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, fumaric acid or maleic acid.

The compounds of the formulas II and III used as starting materials are prepared by methods known per se. For example, a compound of formula (II) is prepared by condensation of the corresponding acylamino-amino compound.

As mentioned above, the novel compounds of the formula I and their physiologically tolerable acid addition salts show valuable pharmacological effects, in addition to anxiolytic action, in particular a cardiovascular action. Thus, compounds of formula I in which A is hydrogen have, in particular, a cardiotonic effect, lowering blood pressure and inhibiting platelet aggregation, and compounds of formula I in which A represents a grouping

Rž

OF

N- (CH 2) n -,

OF

R 3 in particular have an antiarrhythmic effect. In addition, the compounds of formula (I) in which A represents a hydrogen atom are valuable intermediates for the preparation of imidazo-isoquinolinediones substituted in the 5-position by an aminoalkyl radical.

For example, the compounds were investigated as described below

A = 7,7-dimethyl-2- (2,4-dimethoxyphenyl) -5H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione hydrochloride,

B = 7,7-dimethyl-2- (2-methoxy-4-methylsulfonylphenyl) -5H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione,

C = 7,7-dimethyl-2-phenylethyl-5H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione

D = 7,7-dimethyl-2-benzyl-5H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione

E = 7, 4 ', 4', 4 ', 4', 4 ', 4'-yl, 2- (2-methoxyphenyl) -5H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione hydrochloride

F = 7,7-dimethyl-2-cyclohexyl-5H, 7H-imldazo [4,5-h] isoquinoline-4,6-dione

G = 7,7-Dimethyl-14- (4-phenyl) -1H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione hydrochloride

H = 7,7-diethyl-2- (4-methylmercaptophenyl) -5H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione

I = 7,7-Dimethyl-2- (4-methoxyphenyl) -5H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione-hydroxy-4-methoxy-4-iodide

J = 7,7-dimethyl-2- (4-hydroxyphenyl) -5H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione hydrochloride

K = 7,7-dimethyl-2- (2-methoxy-5-methylsulfonylphenyl) -5H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione

L = 7,7-diimethyl-2- (2-methoxy-5-methylsulfinylphenyl) -5H, 7H-imidazo (4,5-h) isoquinoline-4,6-dione hydrochloride; and

M = 7,7-dimethyl-2-cyclopropyl-5H, 7H-imidazo (4,5-h) isoquinoline-4,6-dione hydrochloride, in its cardiotonic effect and blood pressure effect, and the compounds

N = 7,7-dimethyl-2-phenyl-5- (2-diethylaminoethyl) -5H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione dihydrochloride

O = 7,7-dimethyl-2-phenyl-5- (3-diethylaminopropyl) -5H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione dihydrochloride,

P = 7,7-dimethyl-2-phenyl-5- (3-piperidinopropyl) -5H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione dihydrochloride; and

Q = 7,7-dimethyl-2-phenyl-5- (2-dimethylaminoethyl) -5H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione dihydrochloride in terms of its antiarrhythmic effect.

1. Cardiotonic and blood pressure effects

Cats of both sexes, weighing between 2 and 4 kg, are anesthetized by intraperitoneal injection of 30 mg / kg sodium peritobarbital. Arterial blood pressure is measured with a Statham j (P 23 Dc) manometer using a PVC abdominal aorta catheter inserted from the right femoral artery. Ventricular pressure is measured using a catheter-tip manometer (type Millar PC-350) inserted through the carotid artery into the left ventricle, and a derivative amplifier obtains a contractility parameter dp / dt _max . Arterial blood pressure and dp / dt _max are continuously recorded with a direct recorder. Test substances are injected intravenously at a dose of 2 mg / kg. The values are summarized in the following table:

substance blood pressure change increment time of action (mm Hg) (kPa) dp / dt (min / min)

AND —49 / —48 -6.40 / -6.53 +83 > 24 В —52 / —80 -6.93 / -10.7 +76 > 56 C -40 / -50 —5.33 / — 6.67 +87 20 May D —67 / —63 -8.93 / -8.40 +110 > 57 E —46 / —63 -6.13 / -8.40 +77 12 F -23 / -40 -3.10 / -5.33 +86 > 42 G —40 / —30 -5.33 / -4.00 +45 9 H -45 / -45 -6.00 / -6.00 +46 > 12 AND —33 / —46 -4.40 / -6.13 +32 > 19 J -47 / -58 -6.30 / -7.73 +62 > 29 К —70 / —67 -9.33 / -8.93 +157 > 107 L —42 / —53 -5.60 / -7.10 +90 > 70 M -41 / -49 -5.50 / -6.53 +108 > 55

2. Effect on effective refractory period of isolated, electrically irritated guinea pig left atrium

Method:

Guinea pigs of both sexes are killed by a blow to the neck. After opening the chest, their hearts are quickly removed, placed in a 37 ° C Tyrode solution for further processing. Along the Annulus fibrosus, the atria are separated from the ventricles and the left atrium is used. Irritation is performed with a Grass Stimulator (S 4 G, 12 Volt, duration 1 msec, rectangular pulses). The vestibules are embedded in Tyrode's solution (136.8 mval sodium chloride, 2.68 mval potassium chloride, 0.2625 mval magnesium chloride, 0.417 mval primary sodium phosphate, 11.9 mval sodium bicarbonate, 1.8 mval calcium chloride and 3 g of glucose in 1 liter) into which a stream of oxygen / carbon dioxide mixture (98% / 2%) was fed throughout the experiment. The mechanogram is registered isometrically using a polygrafeip Grass P 5 strain gauge. The number of contractions is quantified and compared to the frequency indicated on the stimulator.

First, all frequencies from 1 Hz to the "maximum repetition rate" (1 Hz increments of 10 seconds each) are tested. From the three preliminary experiments, the control value for the "maximum repetition rate" is determined by determining the mean value. Among the individual irritation courses, a "rest pause" is included, during which the irritation is only performed at a frequency of 0.5 Hz.

After determining the control value, the test substance is added to Tyrode's solution and the irritation is continued at 0.5 Hz. The lnotropic effect of the test substance is observed during the first 5 minutes. 5 and 10 minutes after the addition of the test substance, one irritation course was performed. The mean values of the two results (values found after 5 and 10 minutes) are designated as the maximum repetition rate after addition of the test substance. First, small doses are always added, and these are cumulatively replenished to the next higher dose when the maximum repetition rate is determined. the repetition rate for this dose.

Principle:

Tzv. The "maximum repetition rate" is determined by stimulating the heart with increasing frequency irritation. If the interval between two consecutive stimuli is shorter, at a certain irritation frequency, every second pulse falls within the refractory period of the previous cardiac contraction and therefore no contraction occurs. Thus, the "maximum repetition rate" is a measure of the effective refractory period. Substances lowering the "maximum repetition rate" therefore extend the effective refractory period.

For each test substance, the following concentrations were found to reduce the maximum repetition rate to 50 why, control values:

test substance EC 50 in µg / ml N 1,8 O 5.0 P 6.7 Q 4.8

3. Antiarrhythmic effect against chloroform induced ventricular oscillation in mice

The mouse is anesthetized after about 40 seconds when placed in a glass container in which the atmosphere is saturated with chloroform. Breathing ceases and breathing is intermittent after a further 20 seconds. Immediately after intermittent breathing has elapsed, the animal is removed from the container, its heart removed rapidly and cardiac contractions observed. During one-minute observation, almost all the animals undergo spontaneous ventricular oscillation, or that this oscillation can be induced by touching with tweezers.

By prior administration of the antiarrhythmic agent, the vibration rate may be reduced depending on the dose administered. ED 50 values and standard deviations are calculated from dose-response curves (L. C. Miller and M. L. Tainter, Proc. Soc. Exp. Biol. Med. 57, 261 (1944)).

Male mice weighing 20-25 g are used for the test. Each dose is tested on a group of 10 animals.

A dose is determined which, after intravenous or oral administration 1 minute prior to the start of the experiment, prevents ventricular oscillation in 50 o / _o animals.

The results are shown in the following table:

substance ED 50 (mg / kg) oral degree of action ED 50 i v x 100 / ED 50 p. o. intravenous administration (i.v.) oral administration (p. 0.) N 2.4 21.2 11.1% O 6.4 29 22.1% P 10.5 130 8.1% Q 6.1 23.5 26.0%

4. Acute toxicity

Acute toxicity is assessed in groups of mice after administration of various doses of test substances. The dose at which 50% of the animals are killed is determined.

The results are shown in the following table:

the toxicity of cotton, optionally in combination with other active ingredients, to conventional dosage forms such as tablets, dragees, ampoules, solutions, suspensions or suppositories. Compounds of formula I in which A is hydrogen are suitably administered in a unit dose of 50 to 300 mg for the treatment of cardiac insufficiency and hypertension, and compounds of formula I in which A is not hydrogen are administered in unit dose. a dose of 20 to 50 mg is useful for treating cardiac rhythm disorders, particularly in connection with myocardial infarction and angina pectoris.

The invention is illustrated by the following non-limiting examples.

Example 1

7,7-Dimethyl-2-benzyl-5H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione

D> 300 mg / kg (oral)

F> 300 mg / kg (oral)

К> 300 mg / kg (oral)

O LD50: 92 mg / kg (oral) mg / kg (intraperitoneal)

The novel compounds of the formula I and their physiologically tolerable inorganic or organic acid addition salts prepared by the process according to the invention can be treated for pharmaceutical purposes with 204032 g of 2-benzyl-4-carboxy-5- (2-carboxy-2-propyl) benzimidazole. Dissolve in 80 ml of concentrated ammonia, evaporate to dryness, heat the residue at 180 ° C for 1 hour and recrystallize the product from isopropanol. Yield: 4.75 g (56% of theory);

Example 2

7.7-Dimethyl-2-phenyl-5- (3-diethylaminopropyl) -5H, 7H-midazo [4,5-h] isoquinoline-4,6-dione dihydrochloride

4.9 g of 2-phenyl-4-carboxy-5- (2-carboxy-2-propyl) benzimidazole, together with 2.6 g of diethylaminopropylamine and 20 ml of ethylene glycol, were heated at 180 ° C for 1 hour. After cooling, the reaction mixture was diluted with water, extracted twice with chloroform, the chloroform phases were evaporated and the residue was purified by silica gel column chromatography using chloroform / acetone (19: 1) as eluent. The dihydrochloride is precipitated from the acetone solution by addition of ethereal hydrogen chloride.

The yield of the product melting at 205 DEG-208 DEG C. was 5.6 g (76% of theory).

Example 3

7.7-Dimethyl-2-phenethyl-5- (2-methylaminoethyl) -5H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione dihydrochloride

A mixture of 3.0 g of 2-phenethyl-4-carboxy-5- (2-carboxy-2-propyl) benzimidazole, 2 ml of methylaminoethylamine and 15 ml of ethylene glycol was heated at 180 ° C for 2 hours. After distillation of the ethylene glycol in vacuo, the residue is taken up in chloroform, the solution is washed with brine, the chloroform is distilled off, the residue is taken up in acetone and the dihydrochloride is precipitated with methanolic hydrogen chloride.

Yield: 3.2 g (81.2% of theory);

Example 4

7.7-Dimethyl-2- (4-methoxyphenyl) -5- (2-methylaminoethyl) -5H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione dihydrochloride

The above compound was prepared in an analogous manner to Example 3 from 3 g of 2- (4-methoxyphenyl) -4-carboxy-5- (2-carboxy-2-propyl) benzimidazole and 2 ml of methylaminoethylamine. Before precipitation of the dihydrochloride, the product is purified by silica gel column chromatography using chloroform / acetone (19: 1) as eluent.

The yield of the product melting above 260 ° C is

1.1 g (23.6% of theory).

Example 1 a d 5

7.7-Dimethyl-2-phenyl-5- [3- (4-methyl-1-piperazinyl) propyl] -5H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione trihydrochloride

The above compound was prepared in an analogous manner to Example 3 from 1.6 g of 2-phenyl-4-carboxy-5- (2-carboxy-2-propyl) benzimidazole and 0.94 g of 3- (4-methyl-1-piperidine). azinyy) proipylamine.

Yield: 2.5 g (90% of theory);

Example 6

7.7-Dimethyl-2-phenyl-5- (2-dimethylaminoethyl) -5H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione dihydrochloride

The above compound was prepared in an analogous manner to Example 3 from 1.6 g of 2-phenyl-4-carboxy-5- (2-carboxy-2-propyl) benzimidazole and 0.53 g of 2-dimethylaminoethylamine.

The yield of the product melting at 234 DEG-237 DEG C. was 1.5 g (66.8% of theory).

Example 7

7.7-Dimethyl-2-phenyl-5- (2-morpholinoethyl) -5H, 7H-midazo [4,5-h] isoquinoline-4,6-dione dihydrochloride

The above compound was prepared in an analogous manner to Example 3 from

1.6 g of 2-phenyl-4-carboxy-5- (2-carboxy-2-propyl) benzimidazole and 0.78 g of 2-morpholinoethylamine.

Yield: 2 g (81.4% of theory);

Example 8

2.7.7-trimethyl-5- [3- (2- (3,4-dimethoxyphenyl) ethylamino) propyl] -5H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione- difumarate

The above compound was prepared in a manner analogous to Example 2 but without solvent, from 3.4 g of 2-methyl-4-carboxy-5- (2-carboxy-2-propyl) benzimidazole and 3.4 g of 3- [2- (3,4-dimethoxyphenyl) ethylamino] propylamine. The desired difumarate is precipitated from acetone.

The yield of the product melting under decomposition at 134-135 ° C is 5.5 g (61% of theory).

Example 9

7.7-Dimethyl-2-phenyl-5- (3-diethylaminopropyl) -5H, 7H-imieazo [4,5-h] isoquinoline-4,6-dioyl dihydrochioride

1.06 g of 5,7,7-trimethyl-2-phenyl-5H, 7H2 0 4 0 3 2

-imidazo [4,5-h] isoquinoline-4,6-dione and 3 ml of 3-diethylaminopropylamine were heated at 170 ° C for 30 hours. Excess amine was distilled off in vacuo, water was added to the residue and further work-up was carried out as in Example 2.

Yield: 0.29 g (20% of theory);

Example 10

7.7-Dimethyl-2- (2-methoxy-4-methylsulfinylphenyl) -5H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione

To 5.1 g of 7,7-dimethyl-2- (2-methoxy-4-methylmercaptophenyl) -5H, 7H-imidazo [4,5-h] isoquinone-4,6-dione in 100 ml of 70% acid 1.7 g of 30% hydrogen peroxide was added to the acetic acid, and the mixture was allowed to stand at room temperature for a total of 50 hours (of which for the first three hours with stirring). % hydrogen peroxide. The reaction mixture was diluted with water, basified with ammonia, the precipitate was filtered off with suction and the filtrate was extracted twice with chloroform. The chloroform phases are evaporated, the residue is combined with the above precipitate and purified by silica gel column chromatography using chloroform / acetone (19: 1) as eluent.

The yield of the product melting above 260 DEG C. is 3.5 g (66% of theory).

EXAMPLE 11 d-Dihydro-4- (2-methoxy-4-methylsulfonylphenyl) -5H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione

2.3 g of 7,7-dl-methyl-2- (2-methoxy-4-methyl-mercaptophenyl) -5H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione in 70 ml 70% acetic acid is heated to 40 ° C and a total of 10 ml of 30% hydrogen peroxide is added over 10 hours. The reaction mixture was allowed to stand overnight, then diluted with water, basified with ammonia, saturated with sodium chloride and extracted several times with chloroform. The chloroform phases were evaporated and the residue was purified by silica gel column chromatography using chloroform / acetone as eluent (19: 1).

The yield of the product, m.p. &gt; 250 DEG C., is 0.7 g (28% of theory).

Example 12

7.7- 1ϊπι6-2υ1-2- (4-Hydroxyphenyl) -5H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione

A mixture of 2.3 g of 7,7-dimethyl-2- (4-benzyloxyphenyl) -5H, 7H-imidazo [4,5-h] isoquinolin-4,6-dione, 200 ml of methanol and 0.5 g of 10% palladium on carbon was hydrogenated for 4 hours at 50 ° C under 0.5 MPa. The catalyst is filtered off, the filtrate is concentrated by evaporation to a volume of 50 ml and the precipitated crystals are filtered off with suction.

The yield of the product melting above 250 DEG C. is 1.5 g (77.8% of theory).

Example 13

7.7- -1πώθ-1ιυ1-2- (2-methoxy-5-methylsulfonylphenyl) -5H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione

To 8.4 g of 7,7-dimethyl-2- (2-methoxy-5-methylmercaptophenyl) -5H, 7H-midazo [4,5th] isoquinoline-4,6-dione is added 200 ml of glacial acetic acid. 50 ml of water, 2 g of sodium acetate and 10 ml of 30% hydrogen peroxide and the mixture is heated at 50 DEG C. for 10 days with stirring, and an additional 5 ml of 30% hydrogen peroxide is added every two days. The reaction mixture is poured onto ice, neutralized with potassium carbonate, the precipitate is filtered off with suction and recrystallized from ethylene glycol monomethyl ether.

The yield of the product melting above 255 ° C is

2.7 g (22.6% of theory).

Example 14

7.7-Dimethyl-2t (2-methoxy-1-methylsulfinylphenyl) -5H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione

3.0 g of 7,7-dimethyl-2- (2-methoxy-5-methylmercaptophenyl) -5H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione are dissolved in 60 ml of glacial-acetic acid 0.88 ml of 30% hydrogen peroxide is slowly added dropwise at room temperature. The mixture was stirred for a further 30 minutes, then neutralized with a saturated potassium carbonate solution, diluted with water and extracted with chloroform. The chloroform was evaporated and the residue was purified by silica gel column chromatography using chloroform with increasing proportions of acetone as eluent.

The yield of the product, which sintered from 250 DEG C. with heating, is 2.2 g (74% of theory).

The following compounds were also prepared in an analogous manner to the foregoing examples:

7.7-dimethyl-2-phenyl-5H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione hydrochloride, melting above 260 ° C,

7.7-dimethyl-2- (2,4-dimeeoxyphenyl) -5H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione hydrochloride, m.p. 248-249 ° C;

7.7- N-2- [2- (2-methoxy-4-methylmercaptophenyl) -5H, 7H-imidazo [4,5-h] isoquinoline-4,6-7-ionic hydrochloride, melting above 250 ° C,

7,7 · Ρϊπ ^ ϊϊ · · 2,4-2- (2-methoxy-4-indolylsulfinylphenyl) -5H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione, melting above 260 ° C,

7.7-dimethyl-2- (2-methoxy-4-methylsulfonylphenyl) -5H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione, melting above 250 ° C,

2.7.7-trimethyl-5H, 7H-midazo [4,5-h] isoquinoline-4,6-dione hydrochloride, melting above 260 ° C; -mmaiazo [4,5-h] isoquinoline-4-dione-hydro-.

chloride, m.p. 206-207 ° C,

7.7- [4- (4-methylmercaptophenyl) -5H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione, m.p. 251-253 ° C;

7.7-dimethyl-2- (4-methoxyphenyl) -5H, 7H-imidazo [4,5-h] isoquinoline-4,6-7-one hydrochloride, m.p. 282 [deg.] C,

7.7- [1111] 1- [2- (4-hydroxyphenyl) -5H, 7H-imidazo [4,5-h] isoquinol-4-yl] -4,4,6-dione, melting above 250 ° C,

7.7- 6,122-1-2- (4-benzyloxyphenyl) -5H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione hydrochloride, m.p. 244-246 ° C;

7.7-Dimethyl-2- (2-methoxy-5-methylsulfonylphenyl) -1H-1H-imidazo [4,5-h] isoquinoline-4,6-dione, melting above 255 ° C,

7.7-7-Dimethyl-2- (2-indox-5-methylmercaptophenyl) -5H, 7H-imidazole [4,5-h] isoquinoline-4,6-dione hydrochloride, which, when heated, sinters from 210 ° C,

7,7-7-Methyl-2H-5-sulfon-5H, 7H-imidazo [4,5-h] isoceinoline-4,6-7 -ionic acid, melting above 250 ° C,

7,7-7-Dimethyl-2-phenylethyl-5H, 7H-imidazole [4,5-h] isoquinoline-4,6-dione, m.p. 241-243 ° C;

7,7-7-Methyl-2- (2-methoxyphenyl) -5H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione-7-hydrocororide, melting above 250 ° C,

7.7-7-Dimethyl-2-cyclohexyl-5H, 7H-imidazo [4,5-h] isoquinone-4-m.p.

7.7- 7-Methyl-2-cyclopropyl-5H, 7H-imidazo [4,5-h] isoceinolin-4,6-7-ionic chloride which, when heated, sinters from 208 ° C and decomposes at 240 ° C,

7.7-7-Methyl-2- (2-methoxy-15-mdte-lsulphinylphenyl) -SH-1H-imidazo [4,5-h] isoceinolin-4,6-7-ion, which, when heated, sintered from 250 ° C,

2.7.7-trimethyl-5- (3-idythylaminopropyl) -1H-1H-imidazo [4,5-h] isoquinoline-5-thiocyclic acid, melting above 250 ° C;

2,7,7Itrimethyl-5- (2-7-ethylaminoethyl) -5H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione dihydrochloride, melting above 250 ° C,

(7-Chloro-4-dimethylaminoethyl) -5H, 7H-imidazo [4,5-h] isoquinoline

14.6- 7-ionic dihydrochloride, melting above 250 ° C,

7,7I-Methyl-2-benzal-5- (2-morpholin-5-yl) -15H, 7H-imidazo [4,5-h] isoquinone;

7.7-Dimethyl-2-phenyl-dimethyl-5I [2- (2- (3,4-71) methoxyphenyl / ethylamino) ethyl] -5H, 7H-imidazo [4,5-h] isoquinolin-4,6-diimidium hydrochloride, m.p. 207 DEG-210 DEG C.,

7.7- 7-Methyl-2-phenyl-5- (3-piperidinopropyl) -5H, 7H-imidazo [4,5-h] tsoceinolin-

14.6- 7-dione dihadrocelloride, m.p. 234-238 ° C (sinters from 227 ° C),

7,7I-Dimethyl-2- (2-dimethoxyphenyl) -5- (3- (2I / 3,4-climethoxy-phenyl ^/ etealamino) -polyl) -5H, 7H-imiPazo [4,5-h] isoquinone- 4,6-dione dihydrochloride, melting with decomposition at 192 to 194 ° C,

7.7-Dimethyl-2-cyclohexyl-5- (3-piperidin-1-propyl) -5H, 7H-midazo [4,5-h] isoceinol-4,6-dione-7-chlorochloride, m.p. 156-158 ° C;

7.7-dimateal-2-benzyl-5- (3-diethylaminopropyl) -5H, 7H-imidazo [4,5-h] isoquinolin-4,6-dione-7-hydrochloride, m.p. 150-153 ° C (sintered from 130 ° C),

7,7-Dimethyl-2- (4-chlorophenyl) -5- [2- (N-methino- [3,4-dimathoxyphenyl] ethylamino) ethyl] -1H-1H-imidazo [4,5-h] isoquinone -4,6-dione dihydrochloride melting at 230 to 231 ° C with decomposition,

7,77-Dimethyl-2I (4-chlorophenyl) -5- (3-didthyl-aminopropyl) -5H, 7H-midazo [4,5-h] tsocetnoline-4,6-dione-dihydro-chloride, m.p. 206-208 ° C,

7.7- [1- (4-Celophenyl) -5- (2-methyl-1-piperidazolyl) ethyl] -5H, 7H-imidazole [4,5-h] trichloro-4,6-7-thio-triethyl drochloride, melting at 263-266 ° C with decomposition,

7.7- 7-Methyl-2- (2-dimethoxy-4-methylmercaptophenyl) -5- (2-diethylaminomethyl) -5H, 7H-imidazo [4,5-h] isoquinoline-4,6I-7-yl chloride, m.p. 235-238 ° C;

7,77-Dimethyl-2- (4-dimethoxyphenyl) -5I-2--2I / 3,4-dimethoxyphenyl / diethylamino) ethyl] -1H-1H-imidazo [4,5-h] isoquinone ^^ 204032

-dione dihydrochloride, m.p.

210-212 ° C,

7.7-dimethyl-2-phenyl-5- (3-dimethylaminopropyl) -5H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione dihydrochloride, m.p. 234-235 ° C;

7.7-dimethyl-2-cyclopropyl-5- (3-diethyl aminopropyl) -5H, 7H-imidazo [4,5-h] isoquinolin-4,6-dione, melting at 185-187 ° C with decomposition,

7,7-dimethyl-2-phenyl-5- (3-ethylaminopropyl) -5H, 7H-imidazo [4,5-h] isoquinoline-4,6-dione dihydrochloride, m.p. 226-230 ° C.

Claims (5)

A process for the preparation of the novel imidazo-isoquinolinediones of the general formula I in which R 1 is C 1 -C 3 alkyl optionally substituted by phenyl, C 3 -C 6 cycloalkyl or phenyl optionally substituted by one or two substituents, which may be the same or different and are selected from the group consisting of halogen atoms , hydroxyl, methoxy, methylmercapto, methylsulfinyl, methylsulfonyl, and benzyloxy, and A represents a hydrogen atom or a moiety of the formula R2 / - (CH2) _t -N, \ R3 where R 2 represents a hydrogen atom or a C 1 -C 3 alkyl group, R 3 represents an alkyl group having from 1 to 3 3 carbon atoms optionally substituted by a dimethoxyphenyl group; or R 2 and R 3 together with the nitrogen atom to which they are attached form a piperidino, morpholino or piperazino group, the piperazino group being substituted at the position And n is a number of 2 or 3, and their physiologically tolerable addition salts with inorganic or organic acids, characterized in that the dicarboxylic acid of the formula II in which: R 1 is as defined above, or a reactive derivative thereof, reacted with an amine of formula III A — NHz (III) in which A is as defined above, whereupon the optionally obtained compound of formula I in which R 1 is a phenyl group substituted with methylmercapto and / or methylsulfinyl is converted by oxidation to the corresponding methylsulfinyl or methylsulfonyl derivative of formula I, or wherein R 1 represents a phenyl group substituted with a benzyloxy group, optionally converted by debenzylation to the corresponding hydroxy compound of formula I, and / or the compound of formula I obtained is optionally converted into a physiologically tolerable addition salt with an inorganic or organic acid. 2. The process according to item 1, for producing imidazo-isoquinolinediones of the general formula Ia in which R 1 represents an alkyl group having 1 to 3 carbon atoms optionally substituted by a phenyl group, a cycloalkyl group having 3 to 6 carbon atoms or a phenyl group optionally substituted by one or two of the same or different substituents selected from the group consisting of halogen atoms, hydroxyl , methoxy, methylmercapto, methylsulphinyl, methylsulphonyl and / or benzyloxy, and their physiologically tolerable salts with inorganic and organic acids, characterized in that the dicarboxylic acid of the formula IIIa is used as starting material R 1 is as defined above, and ammonia. 3. The process according to item 1, for the preparation of imldazo-isoquinolinediones of the general formula Ib // (ib) in which: R 11 represents an alkyl group having 1 to 3 carbon atoms optionally substituted by a phenyl group, a cycloalkyl group having 3 to 6 carbon atoms or a phenyl group optionally substituted by one or two of the same or different substituents selected from halogen, methoxy and methylmercapto , R 2 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R 3 is C 1 -C 3 alkyl optionally substituted with dimethoxyphenyl, or R 2 and R 3 together with the nitrogen atom to which they are attached form a piperidino, morpholino or piperazino group, wherein the piperazino group at the 4-position is substituted with a C 1 -C 3 alkyl group, and n is 2 or 3, and their physiologically tolerable addition salts with inorganic and organic acids, characterized in that the dicarboxylic acid of the general formula IIb in which: R 1 'is as defined above, or reactive derivative thereof, with an amine of formula IIIb Rz / HaN— (CH2) _n —N \ R3 (IIIb) wherein R2, R3 and n are as defined above, whereupon the compound of formula Ib obtained is optionally converted into a physiologically tolerable addition salt with an inorganic or organic acid. 4. Process according to claim 1, 2 or 3, characterized in that the reaction is carried out in a melt or solvent, at a temperature between 50 and 250 [deg.] C., preferably at the boiling point of tetralin or ethylene glycol. 5. Process according to claim 1, 2 or 4, characterized in that the reaction is carried out in the presence of a water splitting agent, such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid or phosphorus oxychloride.